Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77RQYS)

DOT Name	Hedgehog-interacting protein (HHIP)
Synonyms	HHIP; HIP
Gene Name	HHIP
Related Disease	Chronic obstructive pulmonary disease ( ) Diabetic neuropathy ( ) Hyperglycemia ( ) Nephropathy ( ) Adult glioblastoma ( ) Alzheimer disease ( ) Breast cancer ( ) Carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal adenocarcinoma ( ) Colorectal adenoma ( ) Colorectal cancer ( ) Colorectal cancer, susceptibility to, 1 ( ) Colorectal cancer, susceptibility to, 10 ( ) Colorectal cancer, susceptibility to, 12 ( ) Colorectal neoplasm ( ) Diabetic kidney disease ( ) Gastric cancer ( ) Gastrointestinal stromal tumour ( ) Glioblastoma multiforme ( ) Glioma ( ) Hepatocellular carcinoma ( ) Hereditary hemochromatosis ( ) Hypospadias ( ) Liver cancer ( ) Lung carcinoma ( ) Neoplasm ( ) Non-insulin dependent diabetes ( ) Non-small-cell lung cancer ( ) Obesity ( ) Pancreatic tumour ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary emphysema ( ) Stomach cancer ( ) Type-1/2 diabetes ( ) Advanced cancer ( ) Colorectal carcinoma ( ) Squamous cell carcinoma ( ) Primary biliary cholangitis ( ) Adenocarcinoma ( ) Lung cancer ( ) Metastatic malignant neoplasm ( ) Neuroblastoma ( ) Pancreatitis ( )
UniProt ID	HHIP_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2WFT; 2WFX; 2WG3; 2WG4; 3HO3; 3HO4; 3HO5; 7PGK; 7PGL; 7PGM; 7PGN
Pfam ID	PF07974 ; PF03024 ; PF07995
Sequence	MLKMLSFKLLLLAVALGFFEGDAKFGERNEGSGARRRRCLNGNPPKRLKRRDRRMMSQLE LLSGGEMLCGGFYPRLSCCLRSDSPGLGRLENKIFSVTNNTECGKLLEEIKCALCSPHSQ SLFHSPEREVLERDLVLPLLCKDYCKEFFYTCRGHIPGFLQTTADEFCFYYARKDGGLCF PDFPRKQVRGPASNYLDQMEEYDKVEEISRKHKHNCFCIQEVVSGLRQPVGALHSGDGSQ RLFILEKEGYVKILTPEGEIFKEPYLDIHKLVQSGIKGGDERGLLSLAFHPNYKKNGKLY VSYTTNQERWAIGPHDHILRVVEYTVSRKNPHQVDLRTARVFLEVAELHRKHLGGQLLFG PDGFLYIILGDGMITLDDMEEMDGLSDFTGSVLRLDVDTDMCNVPYSIPRSNPHFNSTNQ PPEVFAHGLHDPGRCAVDRHPTDININLTILCSDSNGKNRSSARILQIIKGKDYESEPSL LEFKPFSNGPLVGGFVYRGCQSERLYGSYVFGDRNGNFLTLQQSPVTKQWQEKPLCLGTS GSCRGYFSGHILGFGEDELGEVYILSSSKSMTQTHNGKLYKIVDPKRPLMPEECRATVQP AQTLTSECSRLCRNGYCTPTGKCCCSPGWEGDFCRTAKCEPACRHGGVCVRPNKCLCKKG YLGPQCEQVDRNIRRVTRAGILDQIIDMTSYLLDLTSYIV
Function	Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.
Tissue Specificity	Widely expressed in fetal and adult tissues. Highest expression in adult heart, liver and pancreas, and in fetal kidney.
KEGG Pathway	cAMP sig.ling pathway (hsa04024 ) Hedgehog sig.ling pathway (hsa04340 ) Pathways in cancer (hsa05200 ) Basal cell carcinoma (hsa05217 )
Reactome Pathway	Ligand-receptor interactions (R-HSA-5632681 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Chronic obstructive pulmonary disease	DISQCIRF	Definitive	Genetic Variation	[1]
Diabetic neuropathy	DISX6VF8	Definitive	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[3]
Nephropathy	DISXWP4P	Definitive	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Genetic Variation	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[8]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[8]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[11]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[15]
Hypospadias	DIS48CCP	Strong	Biomarker	[16]
Liver cancer	DISDE4BI	Strong	Altered Expression	[17]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Pancreatic tumour	DIS3U0LK	Strong	Posttranslational Modification	[21]
Prostate cancer	DISF190Y	Strong	Altered Expression	[22]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[22]
Pulmonary emphysema	DIS5M7HZ	Strong	Genetic Variation	[23]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[15]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[24]
Primary biliary cholangitis	DIS43E0O	Disputed	Biomarker	[25]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[26]
Lung cancer	DISCM4YA	Limited	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[11]
Neuroblastoma	DISVZBI4	Limited	Posttranslational Modification	[27]
Pancreatitis	DIS0IJEF	Limited	Altered Expression	[28]
------------------------------------------------------------------------------------


⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Hedgehog-interacting protein (HHIP).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Hedgehog-interacting protein (HHIP).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Hedgehog-interacting protein (HHIP).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Hedgehog-interacting protein (HHIP).	[32]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Hedgehog-interacting protein (HHIP).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Hedgehog-interacting protein (HHIP).	[34]
Selenium	DM25CGV	Approved	Selenium increases the expression of Hedgehog-interacting protein (HHIP).	[35]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Hedgehog-interacting protein (HHIP).	[36]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Hedgehog-interacting protein (HHIP).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hedgehog-interacting protein (HHIP).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hedgehog-interacting protein (HHIP).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Hedgehog-interacting protein (HHIP).	[41]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Hedgehog-interacting protein (HHIP).	[42]
------------------------------------------------------------------------------------


⏷ Show the Full List of 13 Drug(s)

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hedgehog-interacting protein (HHIP).	[38]
------------------------------------------------------------------------------------

References

1	Correlation between lung cancer and the HHIP polymorphisms of chronic obstructive pulmonary disease (COPD) in the Chinese Han population.Genes Immun. 2019 Apr;20(4):273-280. doi: 10.1038/s41435-018-0033-0. Epub 2018 Jun 19.
2	The role of hedgehog-interacting protein in maintaining cavernous nerve integrity and adult penile morphology.J Sex Med. 2009 Sep;6(9):2480-93. doi: 10.1111/j.1743-6109.2009.01349.x. Epub 2009 Jun 9.
3	Hedgehog Interacting Protein Promotes Fibrosis and Apoptosis in Glomerular Endothelial Cells in Murine Diabetes.Sci Rep. 2018 Apr 13;8(1):5958. doi: 10.1038/s41598-018-24220-6.
4	Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis.IUBMB Life. 2017 Feb;69(2):115-127. doi: 10.1002/iub.1598. Epub 2017 Jan 23.
5	Apolipoprotein E 4 Specifically Modulates the Hippocampus Functional Connectivity Network in Patients With Amnestic Mild Cognitive Impairment.Front Aging Neurosci. 2018 Sep 27;10:289. doi: 10.3389/fnagi.2018.00289. eCollection 2018.
6	Preliminary toxicity results using partial breast 3D-CRT with once daily hypo-fractionation and deep inspiratory breath hold.Radiat Oncol. 2018 Jul 27;13(1):135. doi: 10.1186/s13014-018-1079-x.
7	Overexpression of the HIP gene coding for a heparin/heparan sulfate-binding protein in human thyroid carcinomas.Cancer Res. 1998 Oct 15;58(20):4745-51.
8	Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
9	Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer.J Pathol. 2007 Oct;213(2):131-9. doi: 10.1002/path.2216.
10	Increased urinary excretion of hedgehog interacting protein (uHhip) in early diabetic kidney disease.Transl Res. 2020 Mar;217:1-10. doi: 10.1016/j.trsl.2019.11.001. Epub 2019 Nov 18.
11	Hedgehog Interacting Protein 1 is a Prognostic Marker and Suppresses Cell Metastasis in Gastric Cancer.J Cancer. 2018 Nov 24;9(24):4642-4649. doi: 10.7150/jca.27686. eCollection 2018.
12	Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
13	Epigenetic regulation of human hedgehog interacting protein in glioma cell lines and primary tumor samples.Tumour Biol. 2015 Apr;36(4):2383-91. doi: 10.1007/s13277-014-2846-4. Epub 2014 Nov 22.
14	A novel long noncoding RNA HHIP-AS1 suppresses hepatocellular carcinoma progression through stabilizing HHIP mRNA.Biochem Biophys Res Commun. 2019 Dec 3;520(2):333-340. doi: 10.1016/j.bbrc.2019.09.137. Epub 2019 Oct 8.
15	Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration.Cell Physiol Biochem. 2018;45(5):1840-1850. doi: 10.1159/000487875. Epub 2018 Feb 28.
16	Di-n-butyl phthalate induced autophagy of uroepithelial cells via inhibition of hedgehog signaling in newborn male hypospadias rats.Toxicology. 2019 Dec 1;428:152300. doi: 10.1016/j.tox.2019.152300. Epub 2019 Sep 27.
17	The human HIP gene, overexpressed in primary liver cancer encodes for a C-type carbohydrate binding protein with lactose binding activity.FEBS Lett. 1994 Jan 3;337(1):114-8. doi: 10.1016/0014-5793(94)80640-3.
18	HHIP overexpression inhibits the proliferation, migration and invasion of non-small cell lung cancer.PLoS One. 2019 Nov 25;14(11):e0225755. doi: 10.1371/journal.pone.0225755. eCollection 2019.
19	Lower sarcoplasmic reticulum Ca(2+) threshold for triggering afterdepolarizations in diabetic rat hearts.Heart Rhythm. 2019 May;16(5):765-772. doi: 10.1016/j.hrthm.2018.11.001. Epub 2018 Nov 7.
20	Hhip inhibits proliferation and promotes differentiation of adipocytes through suppressing hedgehog signaling pathway.Biochem Biophys Res Commun. 2019 Jun 18;514(1):148-156. doi: 10.1016/j.bbrc.2019.04.047. Epub 2019 Apr 24.
21	Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms.Cancer Biol Ther. 2005 Jul;4(7):728-33. doi: 10.4161/cbt.4.7.1802. Epub 2005 Jul 4.
22	Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors.BMC Cancer. 2004 Aug 4;4:43. doi: 10.1186/1471-2407-4-43.
23	Evaluation Of HHIP Polymorphisms And Their Relationship With Chronic Obstructive Pulmonary Disease Phenotypes.Int J Chron Obstruct Pulmon Dis. 2019 Oct 3;14:2267-2272. doi: 10.2147/COPD.S213519. eCollection 2019.
24	Prognostic significance of the methylation of Wnt pathway antagonists-CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling-ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas.Clin Oral Investig. 2017 Jun;21(5):1777-1788. doi: 10.1007/s00784-016-1946-5. Epub 2016 Aug 23.
25	The hedgehog pathway regulates remodelling responses to biliary obstruction in rats.Gut. 2008 Sep;57(9):1275-82. doi: 10.1136/gut.2008.148619. Epub 2008 Mar 28.
26	Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas.World J Gastroenterol. 2007 Mar 21;13(11):1659-65. doi: 10.3748/wjg.v13.i11.1659.
27	Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors.Tumour Biol. 2011 Feb;32(1):113-27. doi: 10.1007/s13277-010-0105-x. Epub 2010 Sep 10.
28	Hedgehog Interacting Protein (Hhip) Regulates Insulin Secretion in Mice Fed High Fat Diets.Sci Rep. 2019 Aug 1;9(1):11183. doi: 10.1038/s41598-019-47633-3.
29	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
30	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
31	Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
32	Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
33	Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. Cancer Biol Ther. 2009 Jul;8(14):1328-39. doi: 10.4161/cbt.8.14.8633. Epub 2009 Jul 6.
34	Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
35	Selenium is critical for cancer-signaling gene expression but not cell proliferation in human colon Caco-2 cells. Biofactors. 2007;31(3-4):155-64. doi: 10.1002/biof.5520310302.
36	The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
37	Differential regulation of proliferation, cell cycle control and gene expression in cultured human aortic and pulmonary artery endothelial cells by resveratrol. Int J Mol Med. 2010 Nov;26(5):743-9.
38	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
39	Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
40	Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
41	From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
42	Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.